This invention relates to high purity N-benzyloxycarbonyl-L-aspartic acid (Z-Asp) suitable for the production of L-aspartyl-L-phenylalanine methyl ester (aspartame), an artificial sweetner, and more particularly to an improved method for preparing highly pure Z-Asp from L-aspartic acid (L-AA) and benzylchloroformate (BCF) in the presence of a surfactant and/or a buffer.
As aspartame is known to be about 160 times sweeter than sucrose in aqueous solution, its use as a low-calorie sweetener is highly desirable in many food applications. Aspartame is generally produced using Z-Asp as an intermediate. In view of the end use of the aspartame in food products as a substitute for sugar and other artificial sweeteners, the Z-Asp must be as pure as possible and substantially free of by-products, such as the dipeptide, N-benzyloxycarbonyl aspartyl aspartic acid (Z-Asp-Asp), benzyl chloride, benzaldehyde, dibenzyl carbonate and sodium chloride and are generally formed prior to or during the formation of the Z-Asp.
The condensation reaction of BCF with L-AA in an alkaline medium to yield Z-Asp has been well documented. Prior to 1981, the processes described in the literature did not mention the reaction conditions or suggest any additives needed to produce Z-Asp in high yield with relatively small amounts of by-products.
U.S. Pat. No. 4,293,706 which issued on Oct. 6, 1981 to Gorman, et al. teaches that Z-Asp can be prepared substantially free of Z-Asp-Asp by reacting BCF with the disodium salt of L-AA in an aqueous system within a narrow pH range of between 10.75 to 11.75. The patentees teach broadly that the reaction temperature may be maintained between 10.degree. and 45.degree. C., yet each of the working examples is run at room temperature which they prefer. The reactions are run without any additives which could improve the yields and purity of these products and the rate of the reactions. The patentees caution at column 2, lines 17-25 that when the reaction conditions vary, such as a pH over 12, significant hydrolysis of the benzyl chloroformate occurs and the Z-Asp product contains more than trace amounts of impurities and the yield is reduced. At column 3, lines 15-22, Gorman, et al. also note that as the temperature of the reaction increases, the amount of impurities found in the Z-Asp product tends to increase.
U.S. Pat. No. 4,354,091 issued on Aug. 17, 1982 to Sugiyama, et al. who similarly teach that Z-Asp of high purity can be prepared by reacting BCF with the dialkali metal salt of L-AA by carrying out the reaction with the pH maintained within a narrow range of 12.0 to 13.5 throughout the reaction. Sugiyama, et al. teach maintaining the temperature of the reaction between 0.degree. and 30.degree. C. The sole working example maintains the temperature of the reaction between 10.degree. and 30.degree. C. for three hours. The comparative examples show increased amount of Z-Asp-Asp when the pH falls below 12.0 together with a decrease in yield. Again, these patentees do not suggest the use of additives to promote the reaction.
While both the Gorman, et al. and Sugiyama, et al. patentees are able to provide rather strict pH and temperature reaction conditions for preparing a relatively pure Z-Asp product with relatively small amounts of Z-Asp-Asp by-product, it remains desirable to increase further the yield and purity as well as providing other improvements in the synthesis of Z-Asp. Accordingly, it is desirable to provide a method of preparing Z-Asp product in higher yields and of higher purity with lesser amounts of Z-Asp-Asp, sodium chloride and other impurities then heretofore possible.